Cinnoline derivatives

Abstract

Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are defined in the specification. The compounds are inhibitors of Bruton's tyrosine kinase (BTK). This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders or conditions associated with BTK.

What is claimed is: 
     
       1. A compound of Formula 1, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R l  is hydrogen; 
 R 2  is selected from hydrogen, halo, —CN, C 1-4  alkyl, C 1-4  haloalkyl, —NO 2 , and —OR 14 ; 
 R 3  is selected from hydrogen, halo, —CN, C 1-4  alkyl, C 1-4  haloalkyl, —NO 2 , —OR 14 , and C 2-6  heterocyclyl optionally substituted with from one to three substituents independently selected from halo, hydroxy, oxo, and —CN; 
 R 4  is selected from hydrogen, halo, —CN, C 1-4  alkyl, C 1-4  haloalkyl, —NO 2 , and —OR 14 ; 
 R 5  is a bicyclic C 6-9  heteroaryl having from one to four heteroatoms, each of the heteroatoms being nitrogen, wherein the bicyclic C 6-9  heteroaryl is optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 6 , and R 7 ; 
 each R 6  is independently selected from —OR 8 , —N(R 8 )R 9 , —NR  8 C (O)R 9 , —NHC(O)NR 8 R 9 , —NR 8 C(O)NHR 9 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 )R 9 , —C(O)N(R 8 )OR 9 , —C(O)N( 8 )S(O) 2 R 7 , —N(R 8 )S(O) 2 R 7 , —SR 8 , —S(O)R 7 , and —S(O) 2 N(R 8 )R 9 ; 
 each R 7  is independently selected from
 (a) C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, and R 10 ; and 
 (b) C 3-10  cycloalkyl-(CH 2 ) m —, C 6-14  aryl-(CH 2 ) m —, C 2-6  heterocyclyl-(CH 2 ) m —, and C 1-9  heteroaryl-(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 10 , and C 1-6  alkyl optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, and R 10 ; 
 
 each R 8  and R 9  is independently selected from
 (a) hydrogen; 
 (b) C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, and R 10 ; and 
 (c) C 3-10  cycloalkyl-(CH 2 ) m —, C 6-14  aryl-(CH 2 ) m —, C 2-6  heterocyclyl-(CH 2 ) m —, and C 1-9  heteroaryl-(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 10 , and C 1-6  alkyl optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, and R 10 ; 
 
 each R 10  is independently selected from —OR 11 , —N(R 11 )R 12 , —N(R 11 )C(O)R 12 , —NHC(O)NR 11 R 12 , —NR 11 C(O)MHR 12 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 )R 12 , —C(O)N(R 11 )OR 12 , —C(O)N(R 11 )S(O) 2 R 13 , —NR 11 S(O) 2 R 13 , —SR 11 , —SR 11 , —S(O)R 13 , —S(O) 2 R 13 , and —S(O) 2 N(R 11 )R 12;    
 each R 11  and R 12  is independently selected from
 (a) hydrogen; and 
 (b) C 1-6  alkyl and C 3-10  cycloalkyl-(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, —OH, and —NH 2 ; 
 
 each R 13  is independently selected from C 1-6  alkyl and C 3-10  cycloalkyl -(CH 2 ) m —, each optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, —OH, and —NH 2 ; 
 each R 14  is independently selected from hydrogen, C 1-4  alkyl, and C 1-4  haloalkyl; and 
 each m is independently selected from 0, 1, 2, 3, and 4; 
 wherein each heteroaryl and heterocyclyl moiety of R 3 , R 7 , R 8 , and R 9  independently has one to four heteroatoms, each of the heteroatoms independently selected from N, O, and S. 
 
     
     
       2. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 2 , R 3 , and R 4  are each independently selected from hydrogen, methyl, halo, and —OCH 3 . 
     
     
       3. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein each of R 2 , R 3 , and R 4  is hydrogen. 
     
     
       4. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is a bicyclic C 6-8  heteroaryl having from one to three heteroatoms, each of the heteroatoms being nitrogen, and wherein the C 6-8  heteroaryl is optionally substituted with from one to five substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       5. A compound or pharmaceutically acceptable salt according to  claim 4 , wherein the bicyclic C 6-8  heteroaryl of R 5  is an aromatic ring ortho-fused to a pyrrole, pyrazole, imidazole, triazole, pyrrolidine, pyrazolidine, imidazolidine or triazolidine ring, the aromatic ring is benzene or pyridine, and the bicyclic C 6-8  heteroaryl is optionally substituted with from one to four substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       6. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is selected from indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo [3 ,4-b]pyridinyl, indolyl, isoindolyl, 1H-pyrrolo [3 ,2-b]pyridinyl, 1H-pyrrolo [2,3 -b]pyridinyl, benzimidazolyl, benzotriazolyl, indolinyl, isoindolinyl, and benzimidazolinyl, each optionally substituted with from one to four substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       7. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is selected from 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H- pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 1H-indo1-5-yl, 1H-indol -6-yl, 2H-isoindo1-5-yl, 1H-pyrrolo[3,2-b]pyridin-5-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H- pyrrolo[2,3-b]pyridin-6-yl, 1H-benzo[d]imidazol-5-yl, 1H -benzo[d]imidazol-6-yl, 1H-benzo[d][1,2,3]triazol-5-yl, 1H-benzo[d][1,2,3]triazol-6-yl, indolin-5-yl, indolin-6-yl, isoindolin-5-yl, and 2,3-dihydro-1H-benzo[d]imidazol-5-yl, each optionally substituted with from one to four substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       8. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is selected from 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indol-5-yl, 1H-indol-6-yl, 2H-isoindo1-5-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo [d][1,2,3]triazol-5-yl, 1H-benzo[d][1,2,3]triazol -6-yl, and isoindolin-5-yl, each optionally substituted with from one to four substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       9. A compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 5  is selected from 1H-indazol-5-yl and 1H-indazol-6-yl, each optionally substituted with from one to four substituents independently selected from halo, oxo, —CN, R 6 , and R 7 . 
     
     
       10. A compound or pharmaceutically acceptable salt according to  claim 4 , wherein the bicyclic C 6-8  heteroaryl of R 5  is optionally substituted with from one to three substituents independently selected from halo, oxo, —CN, C 1-4  alkyl, and —OR 8 , wherein R 8  is selected from hydrogen and C 1-4  alkyl. 
     
     
       11. A compound according to  claim 1 , which is selected from the following compounds:
 4-amino-8-(1-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-pyrrolo[3,2-b]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methyl-1H-indo1-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(7-fluoro-2-oxoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methylindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-oxoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methyl-1H-indo1-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(imidazo[1,2-]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-methyl-2H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methyl-1H-benzo[d]imidazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-indo-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-methyl-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-isopropyl-1H-benzo[d]imidazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1-cyclohexyl-1H-benzo[d]imidazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1-tent-butyl-1H-benzo[d]imidazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-oxoindolin-6-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(1H-pyrrolo[3,2-b]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-benzo[c/]imidazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-7-methyl-8-(1-methyl-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-indo-5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(1-methyl-1H-indazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1H-indol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1H-indol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1,4-dimethyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(4-methyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1,7-dimethyl-1H-indazol-5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(7-methyl-1H-indazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)cinnoline-3-carboxamide; 
 4-amino-8-(1-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)cinnoline-3-carboxamide; 
 4-amino-8-(1,3-dimethyl-1H-indazol-5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1,3-dimethyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)-5-methoxycinnoline-3-carboxamide; 
 4-amino-5-methoxy-8-(5-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)-7-methoxycinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)-5-methoxy-7-methylcinnoline -3-carboxamide; 
 4-amino-5-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1,5-dimethyl-1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(1-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1H-benzo[c/]imidazol-6-yl)-7-methoxycinnoline -3-carboxamide; 
 4-amino-7-methyl-8-(1H-pyrazolo[3,4-b]pyridin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1H-benzo [d] [ 1,2,3]triazol-5-yl) -7-methylcinnoline-3-carboxamide; 
 4-amino-8-(6-methyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(3-methyl-1H-indazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1H-indazol-5-yl)-7-methoxycinnoline-3-carboxamide ; 
 4-amino-7-methyl-8-(2-methyl-2H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)-5,7-dimethylcinnoline-3-carboxamide; 
 4-amino-7-chloro-8-(1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1,6-dimethyl-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-5-fluoro-8-(1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(isoquinolin-7-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(isoquinolin-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-5-fluoro-8-(1H-indazol-5-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-7-ethyl-8-(1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-7-ethyl-8-(1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)cinnoline-3-carboxamide; 
 4-amino-6-methyl-8-(5-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-((cyclopropylmethyl)amino)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-neopentyl-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-(3,5-dichlorophenyl)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-cyclohexyl-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-phenethyl-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-(2-chlorophenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-cyclopentyl-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(thiophen-3-yl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(imidazo[1,2-a]pyridin-2-yl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(3-chlorophenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-benzyl-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-(cyclohexylmethyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(thiophen-2-yl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(3,5-dimethylphenyl)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-((tetrahydro-2H-pyran-4-yl)methyl)-1H -benzo[d]imidazol-6-y1)cinnoline-3-carboxamide; 
 4-amino-8-(2-(thiazol-5-yl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(tetrahydro-2H-pyran-3-yl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4,4-difluorocyclohexyl)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)cinnoline-3-carboxamide; 
 4-amino-8-(6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(phenylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(thiophen-2-ylmethylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(cyclobutylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(benzylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4-methylcyclohexylamino)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(benzyl(methyl)amino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(cyclopentylmethylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 8-(2-((adamantan-2-ylmethyl)amino)-1H-benzo[d]imidazol-6-yl)-4-aminocinnoline -3-carboxamide; 
 4-amino-8-(2-(4-methylbenzylamino)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(3-cyano-1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-7-methyl-8-(1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(3-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(3-fluoro-1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(4-fluoro-1H-benzo[d]imidazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(4-fluoro-1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(6-methoxy-1H-indazol-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(7-fluoro-1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(5-chloro-1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(3-cyclopropyl-1H-indazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(5-chloro-1H-indazol-6-yl)-5-fluorocinnoline -3-carboxamide; 
 4-amino-8-(3-chloro-1H-indazol-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-5-fluoro-8-(6-methoxy-1H-indazol-5-yl)cinnoline -3-carboxamide; 
 4-amino-8-(5-methoxy-1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-5-fluoro-8-(5-methoxy-1H-indazol-6-yl)cinnoline -3-carboxamide; 
 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-amino-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(imidazo[1,5-a]pyridin-6-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(imidazo[1,5-a]pyridin-7-yl)-7-methylcinnoline -3-carboxamide; 
 4-amino-8-(2-phenyl-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4-tert-butylphenyl)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(2,4-difluorophenyl)-1H-benzo[d]imidazol -6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4-fluoro-2-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1-oxo-2-phenylisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(1-oxo-2-phenylisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-methyl-l-oxoisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-7-methyl-8-(1-oxoisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-5-fluoro-8-(1-oxoisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-5-fluoro-7-methyl-8-(1-oxoisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(3-hydroxy-3-methylbutyl)-1-oxoisoindolin -5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-(3-hydroxy-3-methylbutyl)-1-oxoisoindolin -5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-7-ethyl-8-(1-oxoisoindolin-5-yl)cinnoline-3-carboxamide; 
 4-amino-8-(2-cyano-1H-benzo[d]imidazol-6-yl)cinnoline -3-carboxamide; 
 4-amino-8-(1-ethyl-1H-benzo[d]imidazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1-ethyl-1H-benzo[d]imidazol-5-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1-(2-cyanoethyl)-1H-benzo[d]imidazol-6-yl)-7-methylcinnoline-3-carboxamide; 
 4-amino-8-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl)-7-methylcinnoline-3-carboxamide ; 
 4-amino-7-cyano-8-(1H-indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-8-(5-methyl-1H-indazol-6-yl)-6-morpholinocinnoline-3-carboxamide; 
 4-amino-6-(4-hydroxypiperidin-l-yl)-8-(5-methyl-1H -indazol-6-yl)cinnoline-3-carboxamide; 
 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline -3-carboxamide; and 
 a pharmaceutically acceptable salt of any of the aforementioned compounds. 
 
     
     
       12. A pharmaceutical composition comprising:
 a compound or pharmaceutically acceptable salt as defined in  claim 1 ; and 
 a pharmaceutically acceptable excipient. 
 
     
     
       13. A combination comprising an effective amount of a compound or pharmaceutically acceptable salt as defined in  claim 1 , and at least one additional pharmacologically active agent. 
     
     
       14. A combination according to  claim 13 , wherein the additional pharmacologically active agent is a DMARD. 
     
     
       15. A combination according to  claim 14 , wherein the DMARD is methotrexate. 
     
     
       16. A method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt as defined in  claim 1 , wherein the disease, disorder or condition is rheumatoid arthritis.